The present invention relates to the use of aziridinyl quinones as potential central nervous system antitumor agents. More particularly, the present invention is concerned with a diaziridinyldi(carboethoxyamino)benzoquinone which has been found to have significant activity as a central nervous system antitumor agent against transplanted tumors in mice.
A recent analysis of murine antitumor test data has indicated that the aziridinylquinones, as a family, possess significant activity against lymphoid leukemia L1210 as well as other transplanted mouse tumor test systems. While the L1210 results were all obtained on an intraperitoneally (IP) implanted tumor, the molecular properties of the compounds appeared to fit some of the requirements suggested by Rall and Zubrod in Annu. Rev. Pharmacol., 2, 109 (1962) as important for central nervous system (CNS) penetration. Subsequent testing of these compounds in several intracerebral (IC) transplanted mouse tumor systems indicated that the aziridinylquinones possessed substantial IC antitumor activity.
However, a major problem associated with almost all of the antitumor active aziridinylquinones is the very low aqueous solubility of the compounds. This has greatly complicated the preparation of a suitable parenteral dosage form. The present invention is concerned with aziridinylquinones having optimized properties as CNS antitumor agents against transplanted tumors in mice. Emphasis has been placed on the study of the effect of nonionic functional groups, since ionic materials have difficulty penetrating the blood-brain barrier. The chemistry used in the synthesis of the compounds of interest is based mainly on the reactions of tetrachlorobenzoquinone, also known as chloranil, and its tetrafluoro analog, fluoranil. Chloranil may be obtained in a well known manner from phenol, p-chlorophenol or p-phenylenediamine by treatment with potassium chlorate and hydrochloric acid. Fluoranil is prepared from chloranil by reaction with calcium fluoride at elevated temperatures.